Total synthesis of polycyclic natural products : synthetic studies on (+)-ineleganolide, (–)-sinulochmodin C, verrillin hydrate, and aleutianamine.

Polycyclic furanocembranoid natural products are a broad and diverse class of marine and terrestrial natural products that have captured and held the attention of the synthetic and biomedical communities for nearly three decades. Their daunting polycyclic molecular architectures, coupled with promising biological activities and intriguing biosynthetic relationships have rendered these natural products as formidable and popular targets for total synthesis. Despite a well-documented and tremendous effort from the synthetic community, only one de novo total synthesis of a natural product of this type had yielded to total synthesis at the outset of this work (ca. 2020). Accordingly, we set out to develop a flexible, bio-inspired strategy that would allow for the total synthesis of diverse furanocembranoid natural products leveraging selective transannular cyclization reactions. Our pioneering efforts in this area eventuated in the total syntheses of (+)-ineleganolide and (–)-sinulochmodin C, two coveted natural products that had previously evaded multiple total synthesis efforts. This synthetic strategy provided expedient access to advanced intermediates poised for conversion to (+)-verrillin and other high oxidation state furanocembranoids. In 2019, Hamann and coworkers disclosed the isolation of a novel polycyclic pyrroloiminoquinone alkaloid, (+)-aleutianamine, from the marine sponge Latrunculia austini. The natural material was found to possess potent and selective cytotoxicity in vitro against a human pancreatic cancer cell line (PANC-1, IC50 = 25 nM). This remarkable and unprecedented alkaloid contains a variety of interesting structural features. These considerations, coupled with the promising initial biological activity of this alkaloid motivated a renewed synthetic interest in pyrroloiminoquinone chemistry, a subfield that had seen little significant progress since the early 2000s. The western portion of the natural product contains the pyrroloiminoquinone moiety common to members of its class, while the eastern region is comprised of two interwoven, heteroatom-adorned bicyclic systems. The synthetic challenges conferred by these features demanded multiple generations of synthetic strategies to complete a convergent and concise total synthesis. Key to the approach was a novel application of a vinylogous Mukaiyama-Michael reaction between a siloxythiophene and a pyrroloquinone monoketal. A sequence of skeletal rearrangements and carbon-nitrogen bond formations then allowed for completion of the total synthesis.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Doctoral

Grantor

Baylor University.

Year dc:date.issued

2024

Author dc:creator

• Tuccinardi, Joey P. (Joseph P.), 1998-

Advisor dc:contributor.advisor

• Wood, John L. (John Louis)

• Synthesis.
• Crystallography.
• Terpenoids.
• Alkaloids.
• Oxidation.
• Macrocycles.

Statement dc:rights

• Baylor University works are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. Contact libraryquestions@baylor.edu for inquiries about permission.

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/2104/13592

OAI identifier oai:identifier

oai:baylor-ir.tdl.org:2104/13592